Discovery of Small Molecules that Induce the Degradation of Huntingtin
Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the aggregation of mutant huntingtin (mHtt), and removal of toxic mHtt is expected to be an effective therapeutic approach. We designed two small hybrid molecules (1 and 2) by linking a ligand for ubiquitin ligase (cellular inhibitor of apoptosis protein 1; cIAP1) with probes for mHtt aggregates, anticipating that these compounds would recruit cIAP1 to mHtt and induce selective degradation by the ubiquitin‐proteasome system. The synthesized compounds reduced mHtt levels in HD patient fibroblasts and appear to be promising candidates for the development of a treatment for HD.
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Two small-molecule TPD strategies have been reported to lower mHTT levels: a small-molecule glue approach inducing proximity between mHTT and MAP1LC3α to target it to autophagy for degradation; and small-molecule PROTACs that recruit mHTT aggregates to E3 ligases from the IAP family, causing proteasomal degradation of the mutant protein.
“In fact, two small-molecule TPD strategies have been reported to lower mHTT levels: a small-molecule glue approach inducing the proximity between mHTT and microtubule-associated protein 1 light chain 3α (MAP1LC3α; also known as LC3) to target it to the autophagy pathway for degradation196; and small-molecule PROTACs that recruit mHTT aggregates to E3 ligases from the IAP family, causing the protea”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [197]
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PROTAC targeted protein degraders: the past is prologue
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- Authors
- Tomoshige, S., Nomura, S., Ohgane, K., Hashimoto, Y., & Ishikawa, M.
- Affiliations
- The University of Tokyo (JP)
- Corresponding author
- Ishikawa, Minoru
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2017-08-09
- Volume
- 56
- Issue
- 38
- Pages
- 11530-11533
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W2735605417
- Cited by
- 144
- References
- 30
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 26 · 2023: 17 · 2022: 28 · 2021: 14 · 2020: 11 · 2019: 11 · 2018: 5
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Platform for Drug Discovery, Informatics, and Structural Life Science
- Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Japan Society for Promotion of Science (25293027 and 17H03996)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Huntington's disease, mutant huntingtin, small molecule drug discovery, cIAP1, ubiquitin ligase, ubiquitin-proteasome system, protein aggregation, hybrid molecules, neurodegenerative disease treatment
- MeSH terms
- Huntingtin Protein, Dose-Response Relationship, Drug, Fibroblasts, HeLa Cells, Humans, Huntington Disease, Ligands, Structure-Activity Relationship, Molecular Structure, Small Molecule Libraries, Drug Discovery
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